Method of forming a conformable solvent-based bandage and coating material

ABSTRACT

Liquid hemostatic coating materials comprise a cyanoacrylate monomer and a solvent system comprising a volatile, non-reactive liquid that is non-stinging and non-irritating to a user. The material forms a coating or bandage in the form of a film that when applied and adhered to a surface or to the skin of a user inhibits the application surface from adhering to another surface.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the priority of U.S. Provisional Application No.60/708,858, filed Aug. 17, 2005, and U.S. Provisional Application No.60/708,898, filed Aug. 17, 2005, both entitled CONFORMABLE SOLVENT-BASEDBANDAGE AND COATING MATERIAL, which are incorporated herein by referencein their entirety.

FIELD OF INVENTION

This invention relates generally to hemostatic coating materials thatare useful for protecting and repairing surfaces such as biologicalsurfaces, including surgical sites, skin and mucous membranes. Thehemostatic liquid adhesive materials are comprised of a polymerizablecyanoacrylate monomer component and a non-stinging, non-irritating,non-reactive, volatile liquid, wherein the generated coating does notadhere to a second surface. The hemostatic liquid adhesive materials mayalso comprise a silane-containing polymer component, and preferably asiloxysilane polymer, to provide enhanced forming.

BACKGROUND OF THE INVENTION

Cyanoacrylates have found use as liquid adhesive bandages, particularlybutyl and octyl cyanoacrylates (U.S. Pat. No. 6,183,593; U.S. Pat. No.6,143,805). These materials provide hemostasis with quick film formationand they are especially useful for closing thin wounds, such as thosecreated by paper or razor cuts. Wounds that are in high flex areas arenot suitable for treatment with cyanoacrylates as they tend to increasescarring, if well adhered, or to delaminate quickly, if not welladhered, due to their intrinsic brittleness. Polydimethylsiloxanes havebeen blended with cyanoacrylates to increase flexibility and elasticity(U.S. Pat. No. 6,746,667, U.S. Pat. No. 6,183,593, U.S. Pat. No.5,140,084). Cyanoacrylates have low moisture vapor transmission ratesand, hence, do not allow water vapor to equilibrate at the wound site toallow for optimum wound healing. Cyanoacrylates are also known for theirability to adhere two surfaces together quickly, which is a benefit formany surgical and repair applications but is problematic for use as ahemostatic agent or a liquid adhesive bandage where the user does notdesire to adhere two biological surfaces or to another object, e.g.finger to finger or foot to floor.

Additionally, cyanoacrylate monomers when used as liquid adhesivebandages have been found to cause patient discomfort when applied to theskin as polymerization rapidly occurs when placed on a wet surface,generating heat. In addressing this problem, U.S. Pat. No. 6,010,714discloses a biocompatible monomer (preferably a cyanoacrylate) with aneffective amount of a heat dissipating liquid or solid to reduce theexothermic polymerization temperature of the cyanoacrylate. For the heatdissipating liquids cited, which include ethers, ketones,chlorofluorocarbons, alkanes, alcohols, alkenes and mixtures thereof,each of these organic solvents would cause stinging or irritation on anopen wound, thus compromising their use in providing patient comfort andenhanced health. Additionally, U.S. Pat. No. 6,010,714 discloses thatthe solvents employed do not affect the polymerization rate of themonomer. Thus, these solvents do not decrease the polymerization rate,and therefore do not mitigate the rapid release of heat over time as themonomer polymerizes.

A category of liquid adhesive bandage has included non-hemostaticalkylsiloxysiloxane-containing polymers admixed with liquidpolydimethylsiloxanes (U.S. Pat. No. 5,103,812 and U.S. Pat. No.4,987,893) which provide non-stinging, non-irritating coating materialsthat allow body fluid evaporation and oxygen transport, while protectingthe body surface from further contamination and desiccation. In anothervariation, alkylsiloxysiloxane-containing polymers are admixed withisooctane to provide similar coating properties (U.S. Pat. No.6,383,502). These coatings have the common disadvantages of loss ofadhesion toward hydrated surfaces, loss of adhesion in higherflexibility areas such as knuckles or knees, and no hemostaticcapability.

Another category of polymer useful as a liquid adhesive bandage with nohemostatic activity, cycloalkyl methacrylate copolymers, has been foundto be soluble in a mixture of liquid polydimethylsiloxanes, iso-octaneand isododecane (U.S. Pat. No. 6,358,503).

U.S. Pat. No. 5,214,093 discloses the use of 50% cyanoacrylate monomer,25% polydimethylsiloxanes and 25%3-methacryloxypropyltris(trimethylsiloxy)silane (TRIS) monomer as anadhesive formulation for nonsurgical blepheroplasty. This compositionraises toxicity and irritation issues as TRIS monomer is applieddirectly on the eyelid to prepare the surface prior to application ofthe cyanoacrylate bonding agent.

SUMMARY

The present invention provides a liquid hemostatic coating material thatcan act as a bandage or dressing to protect or repair wounds andsurgical incisions, or to treat damaged or threatened skin or mucosaltissue when applied in liquid form and air dried on a biologicalsurface, forming an adherent, solid protective coating withoutsignificant stinging or irritation to the skin, tissues or mucousmembranes of the user and where said coating does not adhere to a secondsurface.

In a preferred embodiment, liquid hemostatic coating materials comprisea cyanoacrylate monomer and a solvent system comprising a volatilehydrophobic liquid, that is non-reactive with the cyanoacrylate monomerprior to application, and that is non-stinging and non-irritating to auser. A hemostatic coating is a coating that arrests the flow of blood.A non-stinging liquid is a liquid that does not cause sharp, sudden,momentary pain when placed upon damaged or undamaged skin, or openwounds, and the like. A non-irritating liquid is a liquid that does notcause inflammation or soreness when placed upon damaged or undamagedskin, or open wounds, and the like. A volatile, hydrophobic liquid isone that is not soluble in water and volatilizes at room or bodytemperature.

In a preferred embodiment, the cyanoacrylate monomer is present fromabout 0.1% to about 99.9% by weight, more preferably, the cyanoacrylatemonomer is present from about 0.1 to about 95% by weight, and mostpreferably, the cyanoacrylate monomer is present from about 0.1 to about90% by weight. Preferably, the non-stinging, non-irritating, volatilenon-reactive liquid is present from about 0.1% up to 99.9% by weight,more preferably the volatile non-reactive liquid is present from about5% up to 99.9% by weight, most preferably from about 10% to 99.9% byweight. The material forms a coating or bandage when applied to asurface or the skin of a user.

In a preferred embodiment, the non-stinging, non-irritating, volatile,non-reactive liquid is a low molecular weight linear or cyclic siloxane.Silicone liquids, which are inorganic/organic hybrids, are noted fortheir very low critical surface tensions. When a cyanoacrylate monomeris admixed with a siloxane solvent, such as hexamethyldisiloxane, andsaid solution is applied to a wet surface, the contents of the liquid atthe air interface will be predominantly the silicone liquid. Thissilicone-containing interface thus prevents adhesion of the polymerizingcyanoacrylate to another surface. Furthermore, because of the lowsurface tension of silicone liquids, the mixture will spread easily overa biological surface in comparison to the application of neatcyanoacrylate, which will have a tendency to bead and not flow. Thus,the incorporation of a siloxane liquid with a cyanoacrylate will lead tomore rapid coverage of a damaged area in a shorter time than neatcyanoacrylate.

In another preferred embodiment, the liquid coating materials of thisinvention comprise a silane-containing polymer, preferably asiloxysilane-containing polymer, a cyanoacrylate monomer, and a solventsystem comprising a volatile, non-reactive hydrophobic (non-polar)liquid that is non-stinging and non-irritating to a user. Preferably,the polymer is present from about 0.01% to about 99.5% by weight, morepreferably from about 0.5% to about 70% by weight, most preferably fromabout 1% to about 40%. Additionally, the cyanoacrylate monomer ispresent from about 0.1% to about 99.5% by weight, more preferably, fromabout 0.1 to about 70% by weight, most preferably from about 0.5% toabout 50%. The non-stinging, non-irritating, volatile, hydrophobicliquid is present from about 0.5% to 99.9% by weight, more preferablyabout 5% to 99.5% by weight, most preferably from about 10% to about98.5%. The material forms a coating, bandage or glue in the form of afilm when applied to a surface or the skin of a user, wherein saidsurface does not bond to another surface. The siloxysilane-containingpolymer provides for water and oxygen transport through the polymer filmthat is believed to aid in healing. Without wishing to be bound bytheory, the film is in the form of an interpenetrating polymer network,wherein the cyanoacrylate polymer is interdispersed within thesiloxysilane polymer.

In a preferred embodiment, when a siloxysilane-containing polymer ispresent, the siloxysilane-containing polymer comprises at least onevinyl-containing siloxysilane monomer (about 20 to 85 mole %)copolymerized with monomers that, in polymer form, are not reactive withthe cyanoacrylate monomer prior to application to the surface. Thesenon-reactive monomers may serve the function of increasing adhesion andcohesion of the polymer. The non-stinging, non-irritating, volatile,non-reactive hydrophobic liquid is preferably a volatile, low molecularweight linear or cyclic siloxane.

In another preferred embodiment, siloxysilane monomers according toclaim 5 comprise at least one of:

-   3-methacryloyloxypropyltris(trimethylsiloxy)silane,-   3-methacryloyloxypropylpentamethyldisiloxane,-   3-methacryloyloxypropylbis(trimethylsiloxy)methylsilane,-   3-methacryloyloxypropyltris(vinyldimethylsiloxy)silane,-   3-methacryloyloxymethylbis(trimethylsiloxy)(pentamethyldisiloxanyl)silane,-   3-methacryloyloxyethyltris(pentamethyldisiloxanyl)silane,-   methacryloyloxymethylbis(trimethylsiloxy)methylsilane,-   methacryloyloxymethyltris(trimethylsiloxy)silane,-   3-methacryloyloxypropylheptacyclopentyl-T8-silsesquioxane,-   3-methacryloyloxypropylheptaisobutyl-T8-silsesquioxane,-   3-acryloyloxypropylmethylbis(trimethylsiloxy)silane,-   3-acryloyloxypropyltris(trimethylsiloxy)silane,-   3-methacryloyloxypropyl-1,1,1-triphenyl-3,3-dimethyldisiloxane,-   3-methacrylamidopropyltris(trimethylsiloxy)silane,-   3-acrylamidopropyltris(trimethylsiloxy)silane,-   p-vinylphenyltris(trimethylsiloxy)silane,-   p-vinylbenzyltris(trimethylsiloxy)silane,-   vinyloxyethyltris(trimethylsiloxy)silane,-   vinylnonyldimethyl(trimethylsiloxy)silane,-   vinylnonyltris(trimethylsiloxy)silane,-   vinylmethylbis(trimethylsiloxy)silane,-   vinylpentamethyldisiloxane,-   O-(vinyloxyethyl)-N-(tris [trimethylsiloxy]silylpropyl)urethane,-   vinylphenylbis(trimethylsiloxy)silane,-   vinyltris(dimethylsiloxy)silane,-   vinyltris(trimethylsiloxy)silane,-   vinyl-terminated polydimethylsiloxane,-   polydimethylsiloxane monoacrylate,-   polydimethylsiloxane monomethacrylate,-   polymethylphenylsiloxane monoacrylate,-   polymethylphenylsiloxane monomethacrylate, or-   3-acryloyloxypropyltris(polydimethylsiloxanyl)silane.

In another preferred embodiment the non-stinging, non-irritating,volatile, non-reactive liquid is selected from the group having asolubility parameter from 4.9-12.5 (cal/cm³)^(1/2).

In another preferred embodiment, the non-stinging, non-irritating,volatile, non-reactive liquid is selected from the group having asolubility parameter from 5-10 (cal/cm³)^(1/2).

In yet another embodiment, the non-stinging, non-irritating, volatile,non-reactive liquid comprises volatile linear and cyclic siloxanes, andvolatile polydimethylsiloxanes.

In a preferred embodiment, a coating provides for hemostasis.

In another preferred embodiment, the volatile, non-reactive solvent isan alkane, such as isooctane, octane, neopentane, and the like; volatilefluorocarbons, such as pentafluoropropane, perfluoroheptane,perfluoromethylcyclohexane and the like; or a volatile gas, when usedunder pressure as a solvent, such as carbon dioxide.

In another preferred embodiment, a coating is provided that adheres toits applied surface but does not allow the applied surface to adhere toanother surface.

In another preferred embodiment, a coating is provided that does notgenerate discomfort through generation of stinging or irritation whenthe solvent contacts damaged skin or tissue.

In another preferred embodiment, the non-stinging, non-irritatingsolvent decreases the polymerization rate of the cyanoacrylate monomer,thus decreasing with time the release of its heat of polymerization. Thegreater the concentration of non-stinging, non-irritating solvent, thegreater the reduction in the rate of polymerization and the less heatgenerated with time.

In another preferred embodiment, a coating is provided that does notgenerate discomfort through generation of heat from the polymerizingcyanoacrylate monomer, through volatilization of the non-stinging,non-irritating solvent, when said coating is applied to a surface.Alternatively, by decreasing the concentration of the non-stingingsolvent, cauterization can be effected if it is desired to reduce orkill microorganisms at a wound site.

In another preferred embodiment, a coating is provided that is adherentto hydrated and/or non-hydrated surfaces.

In another preferred embodiment, a coating is provided that remainsadherent to a surface when exposed to external water, soaps, detergents,and skincare products.

In another preferred embodiment, a coating is provided that preventsfurther microorganism or particulate contamination to skin or mucousmembrane wounds or incisions.

In another preferred embodiment, a transparent covering is provided thatdoes not attract or hold dirt and can remain colorless and clear forwound viewing as well as cosmetic attractiveness.

In another preferred embodiment, a coating is provided, that, whenapplied, controls body fluid loss from an abraded area.

In another preferred embodiment, a polymer film is provided which allowsmoisture and oxygen transport.

In another preferred embodiment, a polymer film is provided in whichmedicaments or other active agents may be incorporated for controlleddelivery into targeted areas.

In another preferred embodiment, a coating is provided that, afterapplication to a surface, releases from that surface gradually over timewithout requiring externally applied solvents or other removal methods.

A still further object of this invention is to provide a surgical gluewherein a treated surface will not attach to other surrounding surfaces.

Other aspects of the invention are described infra.

DETAILED DESCRIPTION

The cyanoacrylate monomers, when incorporated into non-stinging,non-irritating, volatile, non-reactive liquids and when polymerized,provide for a fast drying, hemostatic, adherent, non-stinging andnon-irritating liquid adhesive coating or bandage that inhibits adhesionof two surfaces to each other. In the absence of the non-stinging,non-irritating, volatile, non-reactive liquid, considerable discomfortis caused by a volatile organic solvent coming in contact with damagedskin as well as heat generation due to the rapid polymerization of thecyanoacrylate monomer. The non-stinging, non-irritating, volatile,non-reactive liquid of the coating formulation is believed to evaporateduring the polymerization of the cyanoacrylate monomer because of itslow heat of vaporization, thus removing the heat of polymerization fromthe applied surface. Further, when said non-stinging, non-irritating,volatile solvent is a siloxane solvent, such as hexamethyldisiloxane,such compounds that have a low heat of vaporization (46 cal/g) generaterapid coating formation, and hence relief to a user, because of therapid removal of the solvent.

When a siloxysilane-containing polymer is added to the above, acontinuous film is introduced that provides greater skin coverage andadhesion. The siloxysilane polymer also aids in moisture and oxygentransport through the film to the damaged skin. These hemostatic coatingmaterials are particularly useful on slowly bleeding or exudatingwounds.

This liquid hemostatic coating can comprise medicants or other activematerials that can be gradually released onto targeted areas, ifdesired.

The liquid hemostatic coatings, comprised of the cyanoacrylate monomerand non-stinging, non-irritating, volatile solvent, includingincorporation of a siloxysilane-containing polymer, are useful forprotecting or treating skin, nails, tissues, organs and mucousmembranes, e.g. bleeding injuries, surgical sites, skin ulcers, cuts,abrasions, incisions, cold sores, blisters, rashes, abraded gums andother oral surfaces, hemorrhoids and abraded body areas, and othermucosal membrane incisions and wounds. The liquid adhesive materials mayalso be used as surgical glues. They also find application in pediatriccare and veterinary care.

As the liquid hemostatic bandages are non-stinging and non-irritatingand instantly cover exposed nerve endings, pain is reduced immediately.The bandages remain adherent to the skin/mucosal surface for up to 2days or more, relieving pain and gradually lifting off without creatingdamage or irritation.

Compositions

Preferred cyanoacrylate monomers that may be used in this inventioninclude readily polymerizable alpha-cyanoacrylates, including alkylcyanoacrylates, aryl cyanoacrylates, alkoxyalkyl cyanoacrylates, such asn-butyl cyanoacrylate, 2-octyl cyanoacrylate, ethyl cyanoacrylate,methyl cyanoacrylate, n-dodecyl cyanoacrylate, phenyl 2-cyanoacrylate,methoxyethyl 2-cyanoacrylate, and the like. The composition may becomposed of one or more polymerizable cyanoacrylate monomers. Thepreferred cyanoacrylates are n-butyl cyanoacrylate and 2-octylcyanoacrylate, with n-butyl cyanoacrylate being the most preferred.

Preferably, the cyanoacrylate monomer is present from about 0.1% toabout 99.9% by weight, more preferably, the cyanoacrylate monomer ispresent from about 0.1 to about 95% by weight, and most preferably, thecyanoacrylate monomer is present from about 0.1 to about 90% by weight.

The cyanoacrylate monomers of the invention are incorporated into asolvent system comprising non-stinging, non-irritating, volatile,non-reactive liquids, preferably having a solubility parameter fromabout 4.9-12.5 (cal/cm³)^(1/2), preferably from about 5-8(cal/cm³)^(1/2). The non-stinging, non-irritating solvent system cancomprise volatile liquid siloxanes, such as hexamethyldisiloxane (HMDS),octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane,octamethyltrisiloxanes and the like. The most preferred non-stinging,non-burning, volatile solvent system is hexamethyldisiloxane. Othervolatile solvents, including volatile alkanes, such as isooctane,octane, neopentane and the like; volatile fluorocarbons, such aspentafluoropropane, perfluoroheptane, perfluoromethylcyclohexane and thelike; or a volatile gas, such as carbon dioxide, can also be employed,each with varying degrees of user discomfort.

Preferably, the non-stinging, non-irritating, volatile non-reactiveliquid is present from about 0.1% up to 99.9% by weight, morepreferably, the volatile non-reactive liquid is present from about 5% upto 99.9% by weight, and most preferably from about 10% to 99.9% byweight.

The use of these non-stinging, non-irritating, volatile, non-reactiveliquids, simply or in combination, as the primary liquid phase of theliquid coating provides for rapid drying and less coating tackinessduring drying. Notably, the use of these volatile non-reactive liquidsinhibits adhesion of two surfaces to each other while allowing for goodadhesion of the coating to its applied surface. During evaporation, thevolatile non-reactive liquid solvent, having a low surface energy, ispredominantly found on the air interface or “top” surface of thecoating, hence inhibiting the cyanoacrylate from reaching the surface ofthe liquid coating and preventing an adherent bond to other surfacesthat may be present.

Additionally, the use of these non-stinging, non-irritating, volatile,non-reactive liquids, simply or in combination, allows for the liquidadhesive coating that contains reactive cyanoacrylates to be applied bypainting, spraying, pumping, dipping or the like.

In the presence of a siloxysilane-containing polymer, thesiloxysilane-containing polymer component of this invention preferablycomprises addition polymerizable siloxysilanes, which polymers are watervapor and oxygen permeable, and which monomers may be copolymerized withother non-cyanoacrylate reactive monomers to form co- or multi-polymers.Water vapor and oxygen permeability, which are provided by thesiloxysilane-containing polymer component, are important for wound careand prevention of skin/tissue degradation. The water vapor permeabilityprevents desiccation and allows for removal of body waste (sweat), whilethe oxygen permeability may aid in wound healing.

The siloxysilane monomers of the siloxysilane polymers include:

-   3-methacryloyloxypropyltris(trimethylsiloxy)silane (TRIS),-   3-methacryloyloxypropylpentamethyldisiloxane,-   3-methacryloyloxypropylbis(trimethylsiloxy)methylsilane,-   3-methacryloyloxypropyltris(vinyldimethylsiloxy)silane,-   3-methacryloyloxymethylbis(trimethylsiloxy)(pentamethyldisiloxanyl)silane,-   3-methacryloyloxyethyltris(pentamethyldisiloxanyl)silane,-   methacryloyloxymethylbis(trimethylsiloxy)methylsilane-   methacryloyloxymethyltris(trimethylsiloxy)silane-   3-methacryloyloxypropylheptacyclopentyl-T8-silsesquioxane-   3-methacryloyloxypropylheptaisobutyl-T8-silsesquioxane-   3-acryloyloxypropylmethylbis(trimethylsiloxy)silane,-   3-acryloyloxypropyltris(trimethylsiloxy)silane,-   3-methacryloyloxypropyl-1,1,1-triphenyl-3,3-dimethyldisiloxane,-   3-methacrylamidopropyltris(trimethylsiloxy)silane,-   3-acrylamidopropyltris(trimethylsiloxy)silane,-   p-vinylphenyltris(trimethylsiloxy)silane-   p-vinylbenzyltris(trimethylsiloxy)silane,-   vinyloxyethyltris(trimethylsiloxy)silane,-   vinylnonyldimethyl(trimethylsiloxy)silane,-   vinylnonyltris(trimethylsiloxy)silane,-   vinylmethylbis(trimethylsiloxy)silane,-   vinylpentyldisiloxane,-   O-(vinyloxyethyl)-N-(tris [trimethylsiloxy]silylpropyl)urethane,-   vinylphenylbis(trimethylsiloxy)silane,-   vinyltris(dimethylsiloxy)silane,-   vinyltris(trimethylsiloxy)silane,-   vinyl-terminated polydimethylsiloxane,-   polydimethylsiloxane monoacrylate,-   polydimethylsiloxane monomethacrylate,-   polymethylphenylsiloxane monoacrylate,-   polymethylphenylsiloxane monomethacrylate,-   3-acryloyloxypropyltris(polydimethylsiloxanyl)silane, and the like.

These siloxysilane monomers, as polymerized, provide for solubility inthe non-stinging, non-irritating, volatile, non-reactive, hydrophobicsolvent systems of choice.

Other addition polymerizable monomers may also be incorporated into thesiloxysilane-containing polymers of this invention to modify adhesion,cohesion, flexibility, toughness, for instance. Examples of these othermonomers are methyl methacrylate, methyl acrylate, tetrahydrofurfurylmethacrylate, cyclohexyl acrylate, tetrahydrofurfuryl acrylate, n-laurylacrylate, n-lauryl methacrylate, 2-phenoxyethyl acrylate, 2-phenoxyethylmethacrylate, isodecyl acrylate, isodecyl methacrylate, isooctylacrylate, isooctyl methacrylate, isobornyl acrylate, isobornylmethacrylate, benzyl acrylate, benzyl methacrylate, 2-butoxyethylacrylate, n-butyl acrylate, n-butyl methacrylate, ethyl acrylate, ethylmethacrylate, dimethyl itaconate, di-n-butyl itaconate, 2-ethylhexylacrylate, 2-ethylhexyl methacrylate, furfuryl methacrylate, n-hexylacrylate, n-hexyl methacrylate, isobutyl acrylate, isobutylmethacrylate, isopropyl methacrylate, pentyl acrylate and methacrylate,2-pentyl acrylate and methacrylate, 3-pentyl acrylate and methacrylate,2-methyl-1-butyl acrylate and methacrylate, 1-methyl-1-butyl acrylateand methacrylate, 1-methyl-1-pentyl acrylate and methacrylate,2-methyl-1-pentyl acrylate and methacrylate, 3-methyl-1-pentyl acrylateand methacrylate, 2-ethyl-1-butyl acrylate and methacrylate,2-ethyl-1-hexyl acrylate and methacrylate, 3,5,5-trimethyl-1-hexylacrylate and methacrylate, 3-heptyl acrylate and methacrylate, decylacrylate and methacrylate, dodecyl acrylate and methacrylate,α-methylstyrene, p-t-butylstyrene, 4-methoxystyrene, n-octadecylacrylate, n-octadecyl methacrylate, 2-phenylethyl acrylate,2-phenylethyl methacrylate, n-tridecyl methacrylate, vinyl benzoate,vinyl naphthalene, and the like. In addition, fluorinated siloxanes,fluorinated itaconates, fluorinated methacrylates or acrylates, such ashexafluoroisopropyl methacrylate, can be used. Furthermore, dienes suchas butadiene or isoprene and their oligomers, derivatized or not, can beused.

Any hydrophobic or hydrophilic polymerizable monomer can be used as longas the resulting copolymer has desired oxygen and water vaporpermeability, desired adhesion to its applied surface, desired cohesion,and non-reactivity with the cyanoacrylate monomer (until application tothe surface) that is a component of the liquid hemostatic composition ofthis invention.

The siloxysilane polymers can be obtained by free radical polymerizationof the monomers utilized, including thermal free radical polymerization,redox free radical polymerization, photoinitiated free radicalpolymerization, and living radical polymerization. If desired, blockcopolymers can be prepared by living radical polymerization or livinganionic polymerization. Thermal free radical polymerization ispreferred, and an azo free radical initiator is most preferred, such as2,2′-azobis(2-methylbutyronitrile), with polymerization done between70-75° C. in the presence of nitrogen.

The siloxysilane-containing polymers of this invention increase coatingflexibility and durability of the applied adhesive coating. Coatingflexibility allows use of the coatings of this invention on flexibleareas of the body, e.g., knees, knuckles and elbows, as the coating cancomfortably flex with body movement while retaining coating integrity.Durability of the dried coating on its applied surface for at least 2days is desirable.

Non-volatile liquid siloxanes, such as derivatives of polysiloxanes andthe like, may also be used with or without the siloxysilane-containingpolymer of this invention for increased flexibility and durability ofthe applied adhesive coating.

The polymer and monomer components of the invention are incorporatedinto a solvent system comprising volatile hydrophobic liquids,preferably having a solubility parameter between about 5.0-8.0(cal/cm³)^(1/2). Hydrophobic liquids are defined for the purposes ofthis invention as being non-water compatible. The solvent systemcomprises volatile liquid silicones, such as hexamethyldisiloxane(HMDS), octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane,octamethyltrisiloxanes and the like. The solubility parameter ofhexamethyldisiloxane is reported to be 5.7 (cal/cm³)^(1/2) and that ofoctamethylcyclotetrasiloxane as 5.4 (cal/cm³)^(1/2) (see U.S. Pat. No.5,103,812, col. 6). The preferred solvent system ishexamethyldisiloxane. Other volatile solvents, including volatilealkanes, such as isooctane, octane, neopentane and the like; volatilefluorocarbons, such as pentafluoropropane, perfluoroheptane,perfluoromethylcyclohexane and the like; or a volatile gas, such ascarbon dioxide, can also be employed, each with varying degrees of userdiscomfort.

Polymer coatings of the invention cast from liquids containing goodsolvents with solubility parameters of between about 9 to 10(cal/cm³)^(1/2) will function, but are generally slow to dry and remaintacky for extended periods.

The use of these non-stinging, non-irritating, volatile, hydrophobicliquids, simply or in combination, as the primary liquid phase of theliquid hemostatic coating provides for rapid drying and less coatingtackiness during drying. Notably, the use of these volatile hydrophobicliquids inhibits adhesion of two surfaces to each other while allowingfor good adhesion of the coating to its applied surface for woundprotection and repair. During evaporation, the volatile hydrophobicliquid is predominantly found on the air interface or “top” surface ofthe coating because of its low surface energy with air, hence inhibitingthe cyanoacrylate monomer from reaching this surface and reacting toform an adherent bond to other surfaces that may be present.

The liquid hemostatic coating material, composed of thesiloxysilane-containing polymer, cyanoacrylate monomer and solvent, isuseful for protecting or treating skin, tissues, organs, nails, hydratedtissues and mucous membranes, e.g. bleeding injuries, surgical site,skin ulcers, cold sores, cuts, rashes, abrasions, incisions andblisters, abraded gums and other oral surfaces, hemorrhoids and abradedbody areas, and other mucosal membrane incisions and wounds. Saidcoating materials also find application in pediatric care and veterinarycare.

As the liquid hemostatic bandage is non-stinging and non-irritating andinstantly covers exposed nerve endings, pain is reduced immediately. Thebandage remains adherent to the skin/mucosal surface for up to 4 days,relieving pain and gradually lifting off without creating damage orfurther irritation.

Normal unabraded skin loses moisture vapor at an average rate of 200g/m²/day in most areas; the palms of the hand and soles of the feetrespire at an average of 500 g/m²/day. The siloxysilane-containingpolymer liquid hemostatic materials of this invention have moisturevapor transmission rates of 100 to 200 g/m²/day depending on protectivefilm thickness (0.001-0.005 inches), thus preventing both dehydration ofthe wounded area and occlusion of body fluids.

Depending on the particular requirements of the user, the hemostaticcompositions of this invention can be applied by known means, such aswith a spray, pump, swab, rod, sterile brush or medicine dropper.However, in many situations a pump dispensing package is preferred forthe hemostatic composition of this invention. Other modes of applicationare exemplified in U.S. Pat. No. 5,928,611, incorporated by referenceherein in its entirety.

The stability, and thus the shelf-life, of some monomeric cyanoacrylatehemostatic, adhesive compositions can be further enhanced and extendedthrough careful regulation of the packaging, wherein neither thepackaging material nor any additives cause the spontaneouspolymerization of the cyanoacrylate. In certain instances, however,acidic inhibitors, such as sulfur dioxide, are present in thecyanoacrylate monomers to prevent spontaneous polymerization.

Other Variations of the Compositions

Other substances may be added to the liquid material or formulation foradditional plasticization, improved adhesion, or rheology control, andthe like, with the proviso that they do not induce spontaneouspolymerization of the cyanoacrylate monomer.

Typical plasticizer/adhesion promoters are dibutylphthalate, acetyltributyl citrate, sucrose acetate isobutyrate, sucrose benzoate,acetyltriethyl citrate, mineral oil, decamethylcyclopentasiloxane,octamethylcyclotetrasiloxane, poly(methyphenylsiloxane), butyl glycolateand others. The plasticizing agent preferably contains little or nomoisture and should not significantly affect the polymerization of thecyanoacrylate monomer. Suitable plasticizers include polymericplasticizers, such as poly(ethylene glycol) (PEG) esters and capped PEGesters or ethers, polyester glutarates and polyester adipates. Othercompositions are exemplified by U.S. Pat. Nos. 5,259,835 and 5,328,687;5,981,621; 6,143,352; 6,565,840; 6,010,714; 6,217,603; and 5,928,611,all incorporated by reference herein in their entirety.

Typical rheology additives that may be added to the liquid material orformulation are fumed silica, bentonite and other clay derivatives, andthe like, provided that they do not cause polymerization of thecyanoacrylate monomer.

The composition may optionally also include thickeners. Suitablethickeners include, for example, polycyanoacrylates, polycaprolactone,polyorthoesters, polyalkyl acrylates, copolymers of alkyl acrylate andvinyl acetate, poly(alkyl methacrylate)s, and copolymers of alkylmethacrylates and butadiene. Examples of alkyl methacrylates andacrylates are poly(methyl methacrylate), poly(2-ethylhexyl methacrylate)and poly(2-ethylhexyl acrylate), also poly(butyl methacrylate) andpoly(butyl acrylate), also copolymers of various acrylate andmethacrylate monomers, such as poly(butyl methacrylate-co-methylacrylate).

The composition may also optionally include at least a natural orsynthetic rubber or thermoplastic elastomer to impart impact resistance.Suitable rubbers are known to the skilled artisan. Such rubbers include,but are not limited to, dienes, styrenes, acrylonitriles, and mixturesthereof. Examples of suitable rubbers are disclosed in, for example,U.S. Pat. Nos. 4,313,865 and 4,560,723, the disclosures of which arehereby incorporated in their entireties by reference herein.

The compositions may also include pH modifiers to control the rate ofdegradation of the resulting polymer, as disclosed in U.S. Pat. No.6,143,352, the entire disclosure of which is hereby incorporated byreference herein in its entirety.

To improve the cohesive strength of adhesives formed from thecompositions of this invention, difunctional monomeric crosslinkingagents in concentration of less than 2 wt % of the mixture may be addedto the monomer compositions of this invention. Such crosslinking agentsare known such as in U.S. Pat. No. 3,940,362.

The compositions of this invention may further contain fibrousreinforcement and colorants such as dyes, pigments, and pigment dyes.Examples of suitable fibrous reinforcement include PGA microfibrils,collagen microfibrils, and others as described in U.S. Pat. No.6,183,593, the disclosure of which is incorporated by reference hereinin its entirety. Examples of suitable colorants as described in U.S.Pat. No. 5,981,621 include1-hydroxy-4-[4-methylphenylamino]-9,10-anthracenedione (FD+C violet No.2); disodium salt of6-hydroxy-5-[(4-sulfophenyl)oxo]-2-naphthalenesulfonic acid (FD+C YellowNo. 6);9-(o-carboxyphenyl)-6-hydroxy-2,4,5,7-tetraiodo-3H-xanthen-3-one,disodium salt, monohydrate (FD+C Red No. 3); and the like.

The compositions of the present invention may also include one or morepolymerization stabilizers for the cyanoacrylate monomer, preferablyboth at least one anionic vapor phase stabilizer and at least oneanionic liquid phase stabilizer. Such stabilizing agents may alsoinclude mixtures of anionic stabilizing agents and radical stabilizingagents. These stabilizing agents may inhibit premature polymerization.Suitable stabilizers may include those listed in U.S. Pat. No.6,183,593, the disclosure of which is incorporated by reference hereinin its entirety. Furthermore, certain stabilizers may also function asanti-fungal agents.

Medicants

Medicants may be incorporated into the liquid or solid film bandages forready or continual release from the liquid hemostatic adhesive materialcomponents, which allow incorporation of a variety of medicants, andwhich are long lasting and permeable. The addition of a medicant shouldnot facilitate spontaneous polymerization of the cyanoacrylate monomerprior to its application to the surface of a user. Examples of usefulmedicants are fungicides, antibacterial agents, antiviral agents, cellgrowth factors, antibiotics, anti-inflammatory agents, anti-itch agents,anti-infective agents, antitumor agents, blood pressure and heartregulators, steroids and many more.

Tissue growth-promoting agents may be incorporated or suspended into theliquids of this invention to encourage production of new tissue,adhesion of new tissue, cell migration, etc., provided that they do notcause the spontaneous polymerization of the cyanoacrylate monomer. Forexample, cytokines, such as epidermal growth factor, transforming growthfactor (TGF)-alpha, TGF-beta and the like, incorporated into the liquidadhesive film bandage of this invention may facilitate the re-growth ofwounded areas.

As noted above, a biological component may, optionally, be incorporatedwithin the bandage material. When present, the biological component canbe selected from among a variety of effectors that, when present at thesite of injury, promote healing and/or regeneration of the affectedtissue. In addition to being compounds or agents that actually promoteor expedite healing, the effectors may also include compounds or agentsthat prevent infection (e.g., antimicrobial agents and antibiotics),compounds or agents that reduce inflammation (e.g., anti-inflammatoryagents), compounds that prevent or minimize adhesion formation, such asoxidized regenerated cellulose, hyaluronic acid, and compounds or agentsthat suppress the immune system (e.g., immunosuppressants).

Suitable effectors for use with the bandages of the present inventioncan also include sources of growth factors, such as for example,platelets. Platelets are normally found in the blood and play a role inhemostasis and wound healing. During clot formation, the plateletsbecome activated and release growth factors such as PDGF, TGF-β, VEGF,and IGF. Platelets can be separated from blood using techniques such ascentrifugation. When platelet rich plasma is combined with an activator,a platelet clot is created. An activator can be, but is not limited to,thrombin, adenosine diphosphate (ADP), collagen, epinephrine,arachidonic acid, Ristocetin, and combinations thereof.

Activators useful with this invention may have secondary therapeuticactions that contribute to the healing process. For example, Ristocetinnot only stimulates platelet aggregation, but is also an antibiotic. Itacts by inhibiting bacterial cell wall formation and is most efficaciousagainst actively growing bacteria. Since any invasive procedure has thepotential to induce infection, the benefits of including Ristocetin aretwo fold: its presence stimulates clot formation while also providing aprophylactic action against infection. Gram positive bacteria such asstaphylococcus, known to cause hospital-borne infection are susceptibleto treatment with Ristocetin.

The biological additives can either be dissolved and compatible in theliquid hemostatic adhesive formulation or can remain suspended, providedthat they do not cause polymerization of the cyanoacrylate monomer.

Other Applications

The liquid hemostatic adhesive coatings of this invention could be usedfor applications other than human or animal body care. For instance, thecoatings could be used as a membrane, or part thereof, and, as such,could contain conductive additives or other additives to enhance themembrane effectiveness. The coatings incorporating a mildewcide could beused to protect grout in tile surfaces. Other types of active agentswhich may be desirable to incorporate include perfumes, plant growthregulators, plant insecticides, UV and IR absorbers, etc. The liquidadhesive coatings of this invention could also be used to detect latentfingerprint residues or other residues.

The following examples are offered by way of illustration, not by way oflimitation. While specific examples have been provided, the abovedescription is illustrative and not restrictive. Any one or more of thefeatures of the previously described embodiments can be combined in anymanner with one or more features of any other embodiments in the presentinvention. Furthermore, many variations of the invention will becomeapparent to those skilled in the art upon review of the specification.The scope of the invention should, therefore, be determined not withreference to the embodiments illustrated, but instead should bedetermined with reference to the appended claims along with their fullscope of equivalents.

All publications and patent documents cited in this application areincorporated by reference in pertinent part for all purposes to the sameextent as if each individual publication or patent document were soindividually denoted. By their citation of various references in thisdocument, Applicants do not admit any particular reference is “priorart” to their invention.

EXAMPLES

The preparation of the siloxysilane polymers are illustrated below:

Poly(3-methacryloyloxypropyltris(trimethylsiloxy)silane (TRIS)-co-methylmethacrylate-co-isooctyl acrylate (PSS1)—This terpolymer was obtained bythe procedure represented by U.S. Pat. No. 5,103,812, Example 26.

Poly(3-methacryloyloxypropyltris(trimethylsiloxy)silane(TRIS)-co-methylmethacrylate) (PSS2)—This copolymer was obtained by polymerization ofits monomer components in a 25 ml reaction vessel charged with 6 g ethylacetate, 1.8 g (0.004 mol) TRIS, 0.2 g (0.002 mol) methyl methacrylate,and 0.04 g 2,2′-azobis(2-methylbutanenitrile). The polymerization wasrun for 21 hours at 72-75° C. The polymer was precipitated into methanoland dried at 50° C.

Poly(3-methacryloyloxypropyltris(trimethylsiloxy)silane(TRIS)-co-n-butyl methacrylate) (PSS3). This copolymer was obtained bypolymerization of its monomer components in a 25 ml reaction vesselcharged with 6 g ethyl acetate, 1.8 g (0.004 mol) TRIS, 0.2 g (0.0014mol) n-butyl methacrylate and 0.04 g 2,2″-azobis(2-methylbutanenitrile.The polymerization was run for 21 hours at 72-75° C. The polymer wasprecipitated into methanol and dried at 50° C.

Example 1 Butyl Cyanoacrylate Tested with Disiloxane Liquid

n-Butyl cyanoacrylate (BCA) was mixed into hexamethyldisiloxane (HMDS)at about a one to one volume ratio. When this formulation was pipettedonto a glass slide and covered with another glass slide, thecyanoacrylate polymerized as verified by formation and adhesion of thepolymer onto the first applied glass slide. The polymerizedcyanoacrylate containing HMDS did not provide adequate adhesion to asecond covering slide to prevent the two glass slides from being readilypulled apart.

Additionally, a test was conducted for the rate of polymerization as afunction of solvent concentration in order to assess the time intervalfor heat generation upon the polymerization of the cyanoacrylatemonomer. The mixture included n-butyl cyanoacrylate in the presence andabsence of hexamethyldisiloxane. According to U.S. Pat. No. 6,010,714,which utilized a heat dissipating agent in the presence of acyanoacrylate monomer, the heat dissipating agent did not affect therate of polymerization. Utilizing a glass slide containing BCA with noHMDS as the control, polymerization of this neat system occurred in 25seconds. When a 20% BCA solution in HMDS was studied, utilizing the sameamount of BCA as in the control, polymerization occurred in 40 seconds,and decreased the polymerization rate by 60%. Further, when a 5%solution of BCA in HMDS was studied, polymerization occurred in 89seconds, and this dilution decreased the polymerization rate by 256%.Thus, the addition of the non-stinging, non-irritating volatilehexamethyldisiloxane solvent caused polymerization of the cyanoacrylateto occur at a slower rate than that reported by U.S. Pat. No. 6,010,714,allowing the heat of polymerization to be more evenly dissipated. It wasalso found that the addition of the HMDS solvent, which has a lowcritical surface tension, allowed the BCA mixture to flow readily overthe glass surface, whereas the BCA by itself tended to bead because ofits higher critical surface tension. The use of the HMDS would thusfacilitate rapid coverage of a wound site.

Examples 2-6 Butyl Cyanoacrylate Tested with Disiloxane Liquid

n-Butyl cyanoacrylate was mixed into hexamethyldisiloxane at variousconcentrations by weight. Hemostasis ability was tested by pipetting 5μl of pork blood on a microscope slide immediately followed by pipetting5 μl of the liquid hemostatic composition directly on top of the blooddroplet. In addition to hemostasis testing, adhesion of two surfacesthat are pressed together in the presence of the compositions wastested. 5 μl of the compositions was pipetted onto a glass slide,allowed to dry/react for about 10 seconds, and then another glass slidewas pressed onto the coated first slide. After about 1 minute, force wasapplied to the glass slides to pull them apart.

In Examples 2 and 3 with BCA concentrations 30% and less, the BCAadhered well to its applied glass surface but did not adhere to a secondglass surface that was pressed onto the first applied glass surface.Examples 4-6 demonstrate the inherent capability of BCA to adhere twosurfaces to each other when inadequate amounts of the non-stinging,non-irritating, volatile, non-reactive liquid are present, that is, atconcentrations of BCA of 50% and greater.

BCA/HMDS Adhesion to two Ex (wt %) Hemostasis Ability glass surfaces 210 coagulation no 3 30 coagulation no 4 50 explosive coagulation yes 580 explosive coagulation yes 6 100 (no HMDS) explosive coagulation yes

Examples 7-11 Testing of Octyl Cyanoacrylate/polysiloxysilane Solution(SOL))

2-Octyl cyanoacrylate (OCA) was mixed with a solution containingpoly(3-methacryloyloxypropyltris(trimethylsiloxy)silane-co-methylmethacrylate-co-isooctyl acrylate) (PSS1), polyphenylmethylsiloxane andhexamethyldisiloxane. This solution shall be abbreviated as SOL1(solution one) in the following references. The resultant liquidadhesives were cast onto Teflon™ sheet and evaluated for film formingcharacteristics as shown in the following chart.

OCA/SOL1 OCA/SOL1 (solids, Ex (grams) by parts) Film Integrity as caston Teflon ™ 7 0.08/0.91 1:1 film contracts, forms holes 8 0.07/0.1410:1  film contracts, forms discreet clumps 9 0.02/2.19  1:10 filmconforms to Teflon ™ 10 0.02/1.04 1:5 film contracts slightly, conformsto Teflon ™ 11 0.00/1.2  0:1 film conforms to Teflon ™

With higher concentrations of polysiloxysilane to 2-octyl cyanoacrylatethan 1:1 (comparison of Example 7 with Examples 9 and 10), the filmforming characteristics on Teflon™ of the solution are good. The driedsolutions conform to the substrate and form a continuous film. Example11 illustrates the coating of solution 1 by itself.

Examples 12-16 Testing of Butyl Cyanoacrylate/polsiloxysilane Solution(SOL1)

n-Butyl cyanoacrylate (BCA) was mixed into thepolysiloxysilane-co-methyl methacrylate-co-isooctyl acrylate terpolymersolution (SOL1) at four different weight percentages based on percentsolids. These liquid adhesive compositions were then tested.

Hemostasis ability was tested by pipetting 5 μl of beef blood on amicroscope slide immediately followed by pipetting 15 μl of the liquidadhesive composition directly on top of the blood droplet. A “yes”result indicates the blood droplet coagulated in the presence of theadded coating.

Adhesion to skin was tested by pipetting 10 μl of the liquid adhesivecomposition onto a human forearm which had previously been stained withblue food coloring dye. The blue food coloring dye is water soluble and,hence, is readily washed off upon exposure to water (shower, washingdishes, etc). The liquid adhesive compositions, which were applied ontop of the dried blue food coloring, prevent washing off of the bluefood coloring. Once the liquid adhesive compositions are no longerpresent on the forearm, the blue food coloring is readily washed off.Adhesion of the liquid adhesives was determined by the presence of bluefood coloring dye.

BCA to SOL1 Forearm Adhesion Ex (wt % of solids) Hemostasis Ability(days) 12 0 no coagulation 4 13 9 coagulated top surface 3 of blood 1420 coagulated more blood 4 15 30 instant coagulation 4 16 100 explosivecoagulation 2

With this series of tests, Example 15 provided good results with forearmadhesion of 4 days and instant blood coagulation. Examples 13 and 14 arealso useful as liquid adhesive bandages with gentle hemostasisrequirements. It should be noted that n-butyl cyanoacrylate, by itself(Example 16), coagulates blood explosively with considerable burning andremains intact on human forearm skin for only 2 days. For solution 1with no BCA, no hemostasis was observed.

Examples 17-20 Aging Studies

n-Butyl cyanoacrylate or 2-octyl cyanoacrylate was mixed into thepolysiloxysilane solution (SOL1) and placed into a container which wasnon-reactive with the cyanoacrylates. Various weight percentages of thecyanoacrylate (CA) monomer to the polysiloxysilane were evaluated forlonger term compatibility and stability of the cyanoacrylate monomers.The mixed solutions were held at room conditions (20° C.) for anextended period of time and tested at Day 1, Month 2, and Month 5 bypipetting a 10 μl drop from each of the solutions onto a drop of beefblood. Hemostasis ability was determined by whether or not the beefblood clotted upon contact with the mixed solution. Skin adhesion wasdetermined by pipetting 15 μl of each of the mixed solutions, after theyhad been stored for 5 months at 20° C., onto a human forearm.

Hemostasis Ability Skin Adhesion CA/SOL1 Day Month Month Ability Ex (wt% of solids) 1 2 5 Month 5 17 16 wt % BCA yes yes yes 7 days 18 6.5 wt %BCA yes yes yes 7 days 19 16 wt % OCA yes no no 7 days 20 6.5 wt % OCAyes no no 6 days

Examples 17 and 18 were stable for at least 5 months of aging asobserved by continued hemostasis capability and skin adhesion remaininghigh for 7 days duration.

Examples 21-25 MVTR Testing

n-Butyl cyanoacrylate or 2-octyl cyanoacrylate was mixed into thepolysiloxysilane solution (SOL1) and tested for moisture vaportransmission rate (MVTR) and dirt pick-up.

Moisture vapor transmission rate was determined by the rate water vaporpassed through 1.5-2.7 mil thick films over a period of three days.

Dirt pick-up was determined by pipetting 0.25 μl of liquid adhesive ontoa glass slide, drying the adhesive followed by dipping the slide intotopsoil and waving it back and forth several times. The slides were thenexamined under a microscope for dirt particle pick-up.

Burst strength was determined by casting films of the liquid adhesivesin Mason jar bands to produce dried film thickness between 1.5 and 3mils. Weights were deposited on top of each of the films until the filmcracked or broke. The higher the weight load required for burst, thehigher the cohesive strength of the film. Burst strength (cohesivestrength) was increased by 50% with the addition of BCA to thepolysiloxysilane (comparison of Examples 21 and 22 with Example 25) due,at least in part, to formation of an interpenetrating polymer network.

Dirt pick-up Burst CA/SOL1 MVTR (particle Strength Ex (% of solids)(grams/meter²/day) number) (grams) 21 16 wt % BCA 192 37 318 22 6.5 wt %BCA 142 300 23 16 wt % OCA 100 24 6.5 wt % OCA 104 25 0 wt % BCA 164 73200

Dirt pick-up is substantially reduced by the addition of BCA to thepolysiloxysilane solution (SOL1) (Examples 21 and 25). Moisture vaportransmission rates (MVTR) of Examples 21-24 remain in the same range asExample 25, the polysiloxysilane by itself. The polysiloxysilane (PSS1)is known for its good moisture vapor transmission rate and, hence, itsacceptability as a liquid adhesive bandage. Such a product is soldcommercially as Nexcare Spray Liquid Bandage by 3M Consumer Health Care,St. Paul, Minn. 55144-1000. Therefore, it is a positive result that theMVTRs remain high with the cyanoacrylate-containing compositions of thisinvention.

Examples 26-28 Hemostasis and Adhesion Testing

Adhesion of two surfaces that are pressed together in the presence ofthe compositions was tested in the following manner. 15 μl of thecompositions was pipetted onto a glass slide, allowed to dry/react forabout 10 seconds, and then another glass slide was pressed onto thecoated first slide. After about 5 minutes, force was applied to theglass slides to pull them apart. The same procedure was used with humanfingers except only 5 μl of the compositions was tested. Hemostasisability testing was conducted as in Examples 17-20.

Examples 27 and 28 contain the non-stinging, non-irritating, volatilehydrophobic liquid HMDS, hence, preventing adhesion of two surfaces.Whereas, example 26 does not contain the volatile hydrophobic liquid andadhesion to two surfaces does occur.

Adhesion of two surfaces BCA Human Ex (% of solids) Hemostasis AbilityGlass fingers 26 100% BCA explosive coagulation yes yes 27 32% BCA/SOL1coagulation no no 28 16% BCA/SOL1 coagulation no

Examples 29-33 Hemostasis and Adhesion Testing

n-Butyl cyanoacrylate was mixed into the polysiloxysilane solution(SOL1) and was further tested for hemostasis ability and adhesion with abroader range of formulations containing larger quantities of BCA inrelation to the polysiloxysilane solution. Hemostasis ability andadhesion to two surfaces testing was conducted as in Examples 17-20 andExamples 26-28.

Adhesion of two surfaces BCA Human Ex (% of solution by wt) HemostasisAbility Glass fingers 29 10% BCA/SOL1 coagulation no no (50% BCA by %solids) 30 25% BCA/SOL1 coagulation slight no 31 30% BCA/SOL1coagulation slight no 32 40% BCA/SOL1 explosive coagulation moderate 3350% BCA/SOL1 explosive coagulation yes

Compositions containing 40% BCA or lower (Example 29-32) provided goodblood coagulation while inhibiting adhesion of glass or human fingers toeach other. At higher BCA loadings, explosive blood coagulation occurredand glass surfaces were adhered together (such as Example 33), whichprobably indicates human skin and tissue surfaces would also adheretogether if inadvertently touching the composition.

Examples 34-38 Testing of Cyanoacrylate/polsiloxysilane Solution (SOL2)

n-Butyl cyanoacrylate (BCA) was mixed in various portions with asolution containingpoly(3-methacryloyloxypropyltris(trimethylsiloxy)silane-co-methylmethacrylate) (PSS2) and hexamethyldisiloxane. This polysiloxysilanesolution shall be abbreviated as SOL2 (solution two) in the followingreferences. The formulations were tested as follows.

Tack was determined by rubbing an index finger lightly over driedpolymer coating on glass slide and rating on a scale from 0 to 5(0=slippery, 1=smooth, 2=smooth with slight resistance, 3=resistance,4=resistance with slight stickiness, 5=sticky).

Hemostasis ability was tested by pipetting 5 μl of beef blood on amicroscope slide immediately followed by pipetting 5 μl of the liquidhemostatic adhesive composition directly on top of the blood droplet. A“yes” result indicates the blood droplet coagulated in the presence ofthe added hemostatic composition.

Adhesion to skin was tested by pipetting 10 μl of the liquid hemostaticadhesive composition onto a human forearm that had previously beenstained with yellow food coloring dye. The yellow food coloring dye iswater soluble and, hence, is readily washed off upon exposure to water(shower, washing dishes, etc). The liquid hemostatic adhesivecomposition, which was applied on top of the dried yellow food coloring,prevents washing off of the yellow food coloring. Once the liquidhemostatic adhesive composition is no longer present on the forearm, theyellow food coloring is readily washed off. Adhesion of the hemostaticcomposition was determined by the presence of yellow food coloring dye.

BCA to SOL2 Forearm Adhesion Ex (wt % of soln.) Tack Hemostasis Ability(days) 34 5 1 yes, fluid 35 10 1 yes 36 15 1 yes 37 20 1 yes, crusty 3830 1 yes, crusty 3

With this series of tests, Examples 35-38 provided good results withforearm adhesion of 3 days (Example 38), low tack and instant bloodcoagulation. Example 34 is also useful as liquid adhesive bandage withgentle hemostasis requirements.

Examples 39-43 Testing of Cyanoacrylate/polsiloxysilane Solution (SOL3)

n-Butyl cyanoacrylate (BCA) was mixed with a solution containingpoly(3-methacryloyloxypropyltris(trimethylsiloxy)silane-co-n-butylmethacrylate (PSS3) and hexamethyldisiloxane. This polysiloxysilanesolution shall be abbreviated as SOL3 (solution three) in the followingreferences. The formulations were tested as in Examples 34-38.

BCA to SOL3 Forearm Adhesion Ex (wt % of soln.) Tack Hemostasis Ability(days) 39 5 1 yes, 40 10 1 yes 41 15 1 yes 42 20 1 yes 43 30 1 yes,crusty 2

With this series of tests, Examples 39-43 provided reasonable resultswith forearm adhesion of 2 days (Example 43), low tack and instant bloodcoagulation.

Examples 44-47 Butyl Cyanoacrylate Tested with Hydrocarbon Liquid

n-Butyl cyanoacrylate (BCA) was mixed into 2,2,4-trimethylpentane (TMP),a volatile, non-reactive hydrocarbon, to form liquid adhesivecompositions. These liquid adhesive compositions were then tested.Hemostasis ability was tested by pipetting 5 μl of pork blood on amicroscope slide immediately followed by pipetting 5 μl of the liquidadhesive composition directly on top of the blood droplet.

In addition to hemostasis testing, adhesion of two surfaces that arepressed together in the presence of the compositions was tested. 5 μl ofthe compositions was pipetted onto a glass slide, allowed to dry/reactfor about 10 seconds, and then another glass slide was pressed onto thecoated first slide. After about 1 minute, force was applied to the glassslides to pull them apart.

The data suggest that at cyanoacrylate concentrations above 50%(Examples 46 and 47), the positive benefits of incorporated volatile,non-reactive liquid are diminished. Below 50% BCA concentration in TMP(Examples 44 and 45), two glass surfaces do not adhere to each otherwhen the liquid adhesive composition is applied, although the desiredresult of hemostasis does occur.

BCA/TMP Adhesion to two Ex (wt %) Hemostasis Ability glass surfaces 4413.5 coagulation no 45 30 coagulation no 46 50 explosive coagulation yes47 80 explosive coagulation yes

Examples 48-50 Testing of Butyl Cyanoacrylate/polysiloxysilane in2,2,4-trimethylpentane

Butyl cyanoacrylate (BCA) was mixed at various concentrations with asolution containingpoly(3-methacryloyloxypropyltris(trimethylsiloxy)silane-co-methylmethacrylate-co-isooctyl acrylate) (PSS1) and 2,2,4-trimethylpentane(TMP). The polymer was dissolved at 10 wt % solids into the2,2,4-trimethylpentane solvent. Hemostasis ability and adhesion to twosurfaces testing was conducted as in Examples 17-20 and Examples 26-28.

Adhesion of BCA two surfaces Ex (% of solution by wt) Hemostasis AbilityGlass 48  8% BCA/PSS1/TMP coagulation no (40% BCA by % solids) 49 27%BCA/PSS1/TMP coagulation moderate 50 35% BCA/PSS1/TMP explosivecoagulation yes

With this volatile solvent, less than 35% BCA in the polysiloxysilanesolution is necessary to provide non-explosive coagulation (Examples 48and 49). Below 27% is needed to also have non-adhesion of two surfaces(Example 48).

Other Embodiments

The above examples are representative of specific embodiments of thepresent invention. However, many variations are possible. In all forms,the liquid hemostatic coating material of this invention comprises areactive cyanoacrylate monomer and a solvent system comprising avolatile, non-reactive liquid and which can further comprise a polymercomponent containing siloxysilane functional groups. In all cases theinvention provides a method of forming a hemostatic coating on a surfaceby applying a liquid monomeric cyanoacrylate or a liquid monomericcyanoacrylate with or without a polysiloxysilane, in an inert volatilesolvent, to a surface, which may be bloody; and volatilizing the solventsystem, while concurrently polymerizing the cyanoacrylate and attachingit to the applied surface. In the presence of the polysiloxysilane, aninterpenetrating network is presumably formed, generating a strong,cohesive film. For these systems, the cyanoacrylate attaches to theapplied surface providing hemostatic function and the evaporation of thevolatile solvent from the coating formulation prevents adhesion of thecyanoacrylate to a second surface.

REFERENCES

-   U.S. application Ser. No. 09/430,289 filed Oct. 29, 1999-   U.S. Pat. No. 3,940,362 Overhults-   U.S. Pat. No. 4,313,865 Teramoto, et al.-   U.S. Pat. No. 4,560,723 Millet, et al.-   U.S. Pat. No. 4,987,893, Salamone, et al.-   U.S. Pat. No. 5,103,812, Salamone, et al.-   U.S. Pat. No. 5,140,084 Mikuni, et al.-   U.S. Pat. No. 5,214,093 Nell, et al.-   U.S. Pat. No. 5,259,835 Clark, et al.-   U.S. Pat. No. 5,328,687 Leung, et al.-   U.S. Pat. No. 5,928,611 Leung, et al.-   U.S. Pat. No. 5,981,621 Clark, et al.-   U.S. Pat. No. 6,010,714 Leung, et al.-   U.S. Pat. No. 6,143,352 Clark, et al.-   U.S. Pat. No. 6,143,805 Hickey, et al.-   U.S. Pat. No. 6,183,593 Narang, et al.-   U.S. Pat. No. 6,217,603 Clark, et al.-   U.S. Pat. No. 6,358,503 Gerrish-   U.S. Pat. No. 6,383,502 Dunshee, et al.-   U.S. Pat. No. 6,455,064 Narang, et al.-   U.S. Pat. No. 6,479,725 Brothers-   U.S. Pat. No. 6,565,840 Clark, et al.-   U.S. Pat. No. 6,746,667 Badejo, et al.-   S. C. Davis, W. H. Eaglstein, A. L. Cazzaniga, P. M. Mertz,    Dermatologic Surgery, 2001, 27, pp 783-788.-   W. H. Eaglstein, T. P. Sullivan, P. A. Giordano, B. M. Miskin,    Dermatologic Surgery, 2002, 28, pp 263-267.-   A. J. Singer, L. Berrutti, S. A. McClain, Wound Repair and    Regeneration, 1999, 7, pp. 356-361.-   A. J. Singer, M. Nable, P. Cameau, D. D. Singer, S. A. McClain,    Wound Repair and Regeneration, 2003, 11, pp. 181-187.-   C. Vauthier, C. Dubernet, E. Fattal, H. Pinto-Alphandary, P.    Couvreur, Advanced Drug Delivery Reviews, 55, Issue 4, pp 519-548.

1-40. (canceled)
 41. A method of forming a conformable, adherent,hemostatic coating on a surface comprising: applying a liquid coatingmaterial on a surface, said liquid coating material comprising: about0.5 to about 50 wt % polymerizable cyanoacrylate monomer and about 10 toabout 99.9 wt % of a volatile liquid selected from the group consistingof volatile linear and cyclic siloxanes, volatile polydimethylsiloxanes,volatile hydrocarbons, and combinations thereof, wherein said volatileliquid volatilizes at room or body temperature, said volatile liquidbeing present in an amount such that the liquid coating material doesnot adhere first and second glass surfaces, when: (i) the liquid coatingmaterial is applied to a first glass surface, and (ii) a second glasssurface is applied to the first glass surface, having the liquid coatingmaterial disposed there between; and, evaporating said volatile liquidto form a coating having adhesion to bloody, hydrated and non-hydratedsurfaces, for use as a protective coating layer over the surface,wherein said coating is inhibited from adhering to a second surface. 42.The method according to claim 41, wherein the volatile liquid isselected from the group consisting of volatile linear and cyclicsiloxanes, volatile polydimethylsiloxanes, and combinations thereof. 43.The method according to claim 41, wherein the volatile liquid is avolatile linear and cyclic siloxanes.
 44. The method according to claim41, wherein the volatile liquid is hexamethyldisiloxane,octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane,octamethyltrisiloxanes, or a combination thereof.
 45. The methodaccording to claim 41, wherein said polymerizable cyanoacrylate monomercomponent comprises at least one alpha-cyanoacrylate.
 46. The methodaccording to claim 41, wherein said liquid coating material furthercomprises 0.01 to about 99.5% by weight siloxysilane-containing polymer.47. The method according to claim 46, wherein said liquid coatingmaterial comprises from about 1% to about 40% by weightsiloxysilane-containing polymer.
 48. The method according to claim 46,wherein said siloxysilane-containing polymer comprises a polymerizablesiloxysilane monomer and an addition polymerizable monomer differentfrom said polymerizable siloxysilane monomer.
 49. The method accordingto claim 48, wherein said addition polymerizable monomer is selectedfrom vinyl-containing alkyl-siloxysilanes, vinyl-containingalkylarylsiloxysilanes or both.
 50. The method according to claim 48,wherein said polymerizable siloxysilane monomer comprises at least oneof: 3-methacryloyloxypropyltris(trimethylsiloxy)silane,3-methacryloyloxypropylpentamethyldisiloxane,3-methacryloyloxypropylbis(trimethylsiloxy)methylsilane,3-methacryloyloxypropyltris(vinyldimethylsiloxy)silane,3-methacryloyloxymethylbis(trimethylsiloxy)(pentamethyldisiloxanyl)silane,3-methacryloyloxyethyltris(pentamethyldisiloxanyl)silane,methacryloyloxymethylbis(trimethylsiloxy)methylsilanemethacryloyloxymethyltris(trimethylsiloxy)silane3-methacryloyloxypropylheptacyclopentyl-T8-silsesquioxane3-methacryloyloxypropylheptaisobutyl-T8-silsesquioxane3-acryloyloxypropylmethylbis(trimethylsiloxy)silane,3-acryloyloxypropyltris(trimethylsiloxy)silane,3-methacryloyloxypropyl-1,1,1-triphenyl-3,3-dimethyldisiloxane,3-methacrylamidopropyltris(trimethylsiloxy)silane,3-acrylamidopropyltris(trimethylsiloxy)silane,p-vinylphenyltris(trimethylsiloxy)silanep-vinylbenzyltris(trimethylsiloxy)silane,vinyloxyethyltris(trimethylsiloxy)silane,vinylnonyldimethyl(trimethylsiloxy)silane,vinylnonyltris(trimethylsiloxy)silane,vinylmethylbis(trimethylsiloxy)silane, vinylpentamethyldisiloxane,O-(vinyloxyethyl)-N-(tris [trimethylsiloxy]silylpropyl)urethane,vinylphenylbis(trimethylsiloxy)silane, vinyltris(dimethylsiloxy)silane,vinyltris(trimethylsiloxy)silane, vinyl-terminated polydimethylsiloxane,polydimethylsiloxane monoacrylate, polydimethylsiloxanemonomethacrylate, polymethylphenylsiloxane monoacrylate,polymethylphenylsiloxane monomethacrylate, or3-acryloyloxypropyltris(polydimethylsiloxanyl)silane.
 51. The methodaccording to claim 48, wherein said polymerizable siloxysilane monomeris 3-methacryloyloxypropyltris(trimethylsiloxy)silane and said additionpolymerizable monomer is selected from the group consisting of methylmethacrylate, isooctyl acrylate, n-butyl methacrylate, and combinationsthereof.
 52. A method of covering surgical sites, wounds, mucousmembranes, damaged skin, or a bloody, moist and non-moist surface, saidmethod comprising: applying to a surface in need thereof, a liquidcoating material comprising about 0.5 to about 50 wt % polymerizablecyanoacrylate monomer and about 10 to about 99.9 wt % of a volatileliquid selected from the group consisting of volatile linear and cyclicsiloxanes, volatile polydimethylsiloxanes, volatile hydrocarbons, andcombinations thereof, wherein said volatile liquid volatilizes at roomor body temperature, said volatile liquid being present in an amountsuch that the liquid coating material does not adhere first and secondglass surfaces, when: (i) the liquid coating material is applied to afirst glass surface, and (ii) a second glass surface is applied to thefirst glass surface, having the liquid coating material disposed therebetween; and, sealing the surgical sites, wounds, mucous membranes,damaged skin, or a bloody, moist and non-moist surface; wherein saidcoating is inhibited from adhering to a second surface.
 53. The methodaccording to claim 52, wherein said volatile liquid is selected from thegroup consisting of volatile linear and cyclic siloxanes, volatilepolydimethylsiloxanes, and combinations thereof.
 54. The methodaccording to claim 52, wherein said volatile liquid is a volatile linearand cyclic siloxanes.
 55. The method according to claim 52, wherein saidvolatile liquid is hexamethyldisiloxane, octamethylcyclotetrasiloxane,decamethylcyclopentasiloxane, octamethyltrisiloxanes, or a combinationthereof.
 56. The method according to claim 52, wherein said liquidcoating material further comprises: 0.01 to about 99.5% by weightsiloxysilane-containing polymer comprising a polymerizable siloxysilanemonomer and an addition polymerizable monomer different from saidpolymerizable siloxysilane monomer.
 57. The method according to claim56, wherein said liquid coating material comprises from about 1% toabout 40% by weight siloxysilane-containing polymer
 58. The methodaccording to claim 56, wherein said addition polymerizable monomer isselected from vinyl-containing alkyl-siloxysilanes, vinyl-containingalkylaryl-siloxysilanes or both.
 59. The method according to claim 56,wherein said polymerizable siloxysilane monomer comprises at least oneof: 3-methacryloyloxypropyltris(trimethylsiloxy)silane,3-methacryloyloxypropylpentamethyldisiloxane,3-methacryloyloxypropylbis(trimethylsiloxy)methylsilane,3-methacryloyloxypropyltris(vinyldimethylsiloxy)silane,3-methacryloyloxymethylbis(trimethylsiloxy)(pentamethyldisiloxanyl)silane,3-methacryloyloxyethyltris(pentamethyldisiloxanyl)silane,methacryloyloxymethylbis(trimethylsiloxy)methylsilanemethacryloyloxymethyltris(trimethylsiloxy)silane3-methacryloyloxypropylheptacyclopentyl-T8-silsesquioxane3-methacryloyloxypropylheptaisobutyl-T8-silsesquioxane3-acryloyloxypropylmethylbis(trimethylsiloxy)silane,3-acryloyloxypropyltris(trimethylsiloxy)silane,3-methacryloyloxypropyl-1,1,1-triphenyl-3,3-dimethyldisiloxane,3-methacrylamidopropyltris(trimethylsiloxy)silane,3-acrylamidopropyltris(trimethylsiloxy)silane,p-vinylphenyltris(trimethylsiloxy)silanep-vinylbenzyltris(trimethylsiloxy)silane,vinyloxyethyltris(trimethylsiloxy)silane,vinylnonyldimethyl(trimethylsiloxy)silane,vinylnonyltris(trimethylsiloxy)silane,vinylmethylbis(trimethylsiloxy)silane, vinylpentamethyldisiloxane,O-(vinyloxyethyl)-N-(tris[trimethylsiloxy]silylpropyl)urethane,vinylphenylbis(trimethylsiloxy)silane, vinyltris(dimethylsiloxy)silane,vinyltris(trimethylsiloxy)silane, vinyl-terminated polydimethylsiloxane,polydimethylsiloxane monoacrylate, polydimethylsiloxanemonomethacrylate, polymethylphenylsiloxane monoacrylate,polymethylphenylsiloxane monomethacrylate, or3-acryloyloxypropyltris(polydimethylsiloxanyl)silane.
 60. A methodaccording to claim 56, wherein said polymerizable siloxysilane monomeris 3-methacryloyloxypropyltris(trimethylsiloxy)silane and said additionpolymerizable monomer is selected from the group consisting of methylmethacrylate, isooctyl acrylate, n-butyl methacrylate, and combinationsthereof.